TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

Rodríguez-Ruiz, María E.; Rodríguez, Inmaculada; Mayorga, Lina; Labiano, Tania; Barbés, Benigno; Etxeberría, Iñaki; Ponz-Sarvisé, Mariano; Azpilikueta, Arantza; Bolaños, Elixabet; Sanmamed, Miguel F.; Berraondo, Pedro; Calvo, Felipe A.; Barcelos-Hoff, Mary Helen; Perez-Gracia, José Luis; Melero, Ignacio

doi:10.1158/1535-7163.mct-18-0558

Cited by 75 publications

(51 citation statements)

References 54 publications

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“…Moreover, the simultaneous blocking of CD47 and PD-1 can further prevent the immune escape of circulating tumor cell subsets, thereby inhibiting metastasis [161,162]. Rodríguez-Ruiz et al proposed that combined anti-PD1 and anti-CD137 treatment increases granzyme-B secreted by CTLs, indicating an improved cytotoxic effect [163]. RANKL, which blocks NF-κB ligands, can increase the anti-metastatic activity of antibodies targeting PD1/PD-L1, and the combination of anti-PD1 and anti-RANKL agents can recruit NK cells to promote the synergy between NK cells and TILs.…”

Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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“…Promising results were also seen in metastatic CRC models in which TGFβ inhibition sensitized previously unresponsive tumours to anti-PD1 [ 92 ]. RT-induced TGFβ was shown to inhibit abscopal responses even in combination with anti-PD-1 and anti-CD137 mAbs; this was overcome by TGFβ blockade [ 93 ]. TGFβ blockade has also demonstrated promising results in combination with an agonistic OX40 mAb in metastatic breast cancer, where there was a synergistic T-cell dependent response [ 94 ].…”

Section: The Impact Of Myeloid Cell Populations On Rt and Immunotheramentioning

confidence: 99%

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

et al. 2020

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Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50–60% of patients. It is part of therapy for around 40% of cancer patients who are cured of their disease. Until recently, the focus of this anti-tumour efficacy has been on the direct tumour cytotoxicity and RT-induced DNA damage. Recently, the immunomodulatory effects of RT on the tumour microenvironment have increasingly been recognized. There is now intense interest in potentially using RT to induce an anti-tumour immune response, which has led to rethinking into how the efficacy of RT could be further enhanced. Following the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology (IO) agents has emerged and established immunotherapy as a routine part of cancer treatment. Despite ICI improving outcomes in many cancer types, overall durable responses occur in only a minority of patients. The immunostimulatory effects of RT make combinations with ICI attractive to potentially amplify anti-tumour immunity resulting in increased tumour responses and improved outcomes. In contrast, tumours with profoundly immunosuppressive tumour microenvironments, dominated by myeloid-derived cell populations, remain a greater clinical challenge and RT may potentially further enhance the immunosuppression. To harness the full potential of RT and IO agent combinations, further insights are required to enhance our understanding of the role these immunosuppressive myeloid populations play, how RT influences these populations and how they may be therapeutically manipulated in combination with RT to improve outcomes further. These are exciting times with increasing numbers of IO targets being discovered and IO agents undergoing clinical evaluation. Multidisciplinary research collaborations will be required to establish the optimal parameters for delivering RT (target volume, dose and fractionation) in combination with IO agents, including scheduling to achieve maximal therapeutic efficacy.

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“…Many studies have confirmed the immunomodulatory effects of local therapy; radiotherapy promotes the immunological system by inducing immunogenic cell death and subsequently increasing the sensitivity of lymphocytes to tumor cells [37,[47][48][49][50]. Studies also have demonstrated that the abscopal effect of local treatment combined with immunotherapy enhances the efficacy of treatment for breast cancer cases in animal models [51].…”

Section: Discussionmentioning

confidence: 95%

Saving the Breast Saves the Lives of Breast Cancer Patients

Akbari

Khayamzadeh

Moradi

et al. 2020

International Journal of Surgical Oncology

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Introduction. Surgery has been known as the procedure of choice for breast cancer management since 1700 years before Christ. Nowadays, breast-conserving surgery and mastectomy are performed in selected cases with specific clinical criteria. Here, we compare these two procedures for breast cancer patients with variable features in Cancer Research Center, Tehran, as a single institution experience. Methods. In this 25-year follow-up retrospective cohort study, we identified breast cancer patients who had undergone breast-conserving therapy or mastectomy. Disease-free survival and overall survival were evaluated using Kaplan–Meier survival analysis and the log-rank test between the two groups. A p value less than 0.05 was considered statistically significant. Results. A total of 3358 breast cancer patients, including 61% breast-conserving therapy and 39% mastectomy cases were identified, with a mean follow-up time of 94 months. The overall survival and disease-free survival of all cases were significantly better in breast-conserved patients, particularly in early-stage breast cancer with favorable clinical, pathological, and biological features. Ten-year disease-free survival and overall survival in breast-conserving therapy and mastectomy cases were 74%, 88% and 58%, 80%, respectively. Conclusion. Breast-conserving surgery and radiation therapy prove to be an appropriate treatment option for breast cancer patients in terms of overall survival and disease-free survival when indicated.

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TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

Cited by 75 publications

References 54 publications

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

Saving the Breast Saves the Lives of Breast Cancer Patients

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